Role of Innate Immunity in Transplantation Tolerance

通过Toll样受体（TLR）的先天免疫是抵抗微生物入侵的第一道防线， 对病原体检测至关重要我们的初步数据，使用实验鼠系统，也 表明TLR依赖性免疫对于同种免疫应答是重要的， 树突状细胞（DC）的最大功能，特别是促炎细胞因子的产生， 随后启动TH1同种免疫。虽然这些影响对于拒绝未成年人至关重要， 不匹配的皮肤同种异体移植物，它们对于完全同种异体皮肤和心脏移植物的排斥不是必需的。 同种异体移植然而，先天性免疫在移植耐受中的作用仍然未被探索。由于 先前的报告，使用非移植体外模型，证明了调节性T细胞（T reg）功能 在TLR刺激的DC存在的变化中，我们的初步数据调查了先天性TLR刺激的DC的影响。 并显示缺乏MyD88，一种重要TLR信号 适配器，是关键的耐受诱导。我们提供的证据表明，这是通过监管 与CD4+CD25+ T细胞数量增加和CD4 + CD25+ T细胞数量减少相关的机制 促炎环境。因此，该提议将采用鼠实验移植模型， 将研究先天免疫缺陷促进移植耐受的机制。目的 本提案的第1部分将研究MyD88的缺失是否与耐受性协同作用 方案（共刺激阻断），使平衡向耐受而不是免疫倾斜， 增加T细胞的生成和功能。目的2将研究MyD88缺陷， 减少促炎细胞因子环境，增加T效应子对调节的易感性 导致耐受性诱导。因此，这项建议将严格解决是否缺乏 先天性MyD88信号传导促进移植耐受性，这是免疫学领域中以前未探索的概念。 移植所产生的信息将支持移植领域的新范式， 具有提供可转化为人类同种异体移植的未来治疗的潜力， 自身免疫（例如，在耐受性诱导时MyD88阻断）。

Innate immunity via Toll Like Receptors (TLRs) is the first line of defense against microbial invasion and is essential for pathogen detection. Our preliminary data, using experimental murine systems, also demonstrates that TLR dependent immunity is important for alloimmune responses by allowing the maximal function of dendritic cells (DCs), specifically the production of proinflammatory cytokines that subsequently initiate TH1 alloimmunity. Although these effects are critical for the rejection of minor mismatched skin allografts they are not essential for the rejection of fully allogeneic skin and cardiac allografts. However, the role of innate immunity in transplantation tolerance remains unexplored. Since a prior report, using non-transplant in vitro models, demonstrated that T regulatory cell (T reg) function changes in the presence of TLR stimulated DCs, our preliminary data investigate the impact of innate immunity on transplantation tolerance and show that absence of MyD88, an important TLR signal adaptor, is critical for tolerance induction. We provide evidence that this occurs via a regulatory mechanism that is associated with increased numbers of CD4+CD25+ T cells and a reduced proinflammatory milieu. Therefore, this proposal will employ a murine experimental transplant model and will examine the mechanisms by which defective innate immunity facilitates transplantation tolerance. Aim 1 of this proposal will examine whether the absence of MyD88 operates in synergy with the tolerance protocol (costimulatory blockade), tipping the balance towards tolerance rather than immunity, by increasing the generation and function of T regs. Aim 2 will investigate whether MyD88 deficiency, by reducing the proinflammatory cytokine environment, increases T effector susceptibility to regulation leading to tolerance induction. Therefore, this proposal will critically address whether an absence of innate MyD88 signaling promotes transplantation tolerance, a previously unexplored concept in the field of transplantation. The information generated will support a new paradigm in the field of transplantation and has the potential to provide future therapeutics translatable to human allograft transplantation and autoimmunity (e.g., MyD88 blockade at the time of tolerance induction).